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Monday, October 13, 2014

Inflammation, the Immune System, and the Brain - New Models of Disease

In recent years, science is finally beginning to grasp the obvious
fact that the human body is a system, so that when something goes wrong
in one part of the organism, it has effects in other parts of the
organism as well. The most obvious example of this is the new focus on
the microbiome (the enteric nervous system and the flora that inhabit it) and its relation to physical and mental health.

The
microbiome is also where the heart of the immune system resides. When
the "gut" is not healthy, the immune system is not healthy, which leads
to higher levels of inflammation.

One of the key issues
researchers are focusing on is inflammation - a normal and healthy
response to a wound or exposure to a pathogen, but not so healthy when
levels of inflammation remain elevated for long periods of time (which
can happen when we are under chronic stress conditions).

Inflammation
has been linked to Alzheimer's Disease, diabetes, depression, damaged
memory retrieval, schizophrenia, and many other physical and
psychological issues.

Here are some recent articles on
the intersection of the immune system and mental health and the role of
inflammation, and specifically neuroinflammation, on the brain and the
mind. These are arranged from easiest to read to the more technical
research at the bottom of the post.

Summary: Children with high everyday levels of a protein released into the blood in response to infection are at greater risk of developing depression and psychosis in adulthood, according to new research that suggests a role for the immune system in mental illness. The study indicates that mental illness and chronic physical illness such as coronary heart disease and type 2 diabetes may share common biological mechanisms.___

A team of scientists led by the University of Cambridge studied a sample
of 4,500 individuals from the Avon Longitudinal Study of Parents and
Children -- also known as Children of the 90s -- taking blood samples at
age 9 and following up at age 18 to see if they had experienced
episodes of depression or psychosis. The team divided the individuals
into three groups, depending on whether their everyday levels of IL-6
were low, medium or high. They found that those children in the 'high'
group were nearly two times more likely to have experienced depression
or psychosis than those in the 'low' group.

Elevated levels of C-reactive protein in pregnant women are strongly
linked to an increased risk for schizophrenia in offspring, new research
shows.

A nested case-control study showed that increasing
maternal levels of C-reactive protein, a well-established and reliable
marker of inflammation, were associated with a nearly 60% increased
risk for schizophrenia in children. The finding remained significant
after adjusting for a wide range of potential confounders, including
parental history of mental illness.

"This ﬁnding provides the most
robust evidence to date that maternal inﬂammation may play a signiﬁcant
role in schizophrenia, with possible implication for identifying
preventive strategies and pathogenic mechanisms in schizophrenia and
other neurodevelopmental disorders," the authors, led by Sarah Cannetta,
PhD, Columbia University and New York State Psychiatric Institute in
New York City, write.

The study is published in the September issue of the American Journal of Psychiatry.

Elevated
levels of C-reactive protein in pregnant women are strongly linked to
an increased risk for schizophrenia in offspring, new research shows.

A
nested case-control study showed that increasing maternal levels of
C-reactive protein, a well-established and reliable marker of
inflammation, were associated with a nearly 60% increased risk for
schizophrenia in children. The finding remained significant after
adjusting for a wide range of potential confounders, including parental
history of mental illness.

"This
ﬁnding provides the most robust evidence to date that maternal
inﬂammation may play a signiﬁcant role in schizophrenia, with possible
implication for identifying preventive strategies and pathogenic
mechanisms in schizophrenia and other neurodevelopmental disorders,"
the authors, led by Sarah Cannetta, PhD, Columbia University and New
York State Psychiatric Institute in New York City, write.

The study is published in the September issue of the American Journal of Psychiatry.

Chronic inflammation has been shown to contribute to the development of a
wide variety of disorders by means of a number of proposed mechanisms.
Depression and cognitive impairment are two such disorders which may
share a closely linked inflammatory etiology. The ability of
inflammatory mediators to alter the activity of enzymes, from key
metabolic pathways, may help explain the connection between these
disorders. The chronic up-regulation of the kynurenine pathway results
in an imbalance in critical neuroactive compounds involving the
reduction of tryptophan and elevation of tryptophan metabolites. Such
imbalances have established implications in both depression and
cognitive impairment. This may implicate the immune system as a
potential therapeutic target in the treatment of these disorders. The
most common treatment modalities currently utilized, involve drug
interventions which act on downstream targets. Such treatments help to
reestablish protein balances, but fail to treat the inflammatory basis
of the disorder. The use of anti-inflammatory interventions, such as
regular exercise, may therefore, contribute to the effectiveness of
current drug interventions in the treatment of both depression and
cognitive impairment.

Similar to peripheral immune/inflammatory cells, neuroglial cells appear
to rely on calcineurin (CN) signaling pathways to regulate cytokine
production and cellular activation. Several studies suggest that harmful
immune/inflammatory responses may be the most impactful consequence of
aberrant CN activity in glial cells. However, newly identified roles for
CN in glutamate uptake, gap junction regulation, Ca2+ dyshomeostasis,
and amyloid production suggest that CN’s influence in glia may extend
well beyond neuroinflammation. The following review will discuss the
various actions of CN in glial cells, with particular emphasis on
astrocytes, and consider the implications for neurologic dysfunction
arising with aging, injury, and/or neurodegenerative disease.

The human brain- and retinal-resident microRNA-146a (miRNA-146a) is an
inducible, NF-kB-regulated small non-coding RNA (sncRNA) whose increased
expression is associated with pro-inflammatory neurodegeneration in
Alzheimer’s disease (AD), age-related macular degeneration (AMD), and
prion disease (PrD). In AD, AMD, and PrD miRNA-146a modulates the
innate-immune response, inflammation, and the microglial activation
state. This short paper will review and comment on the role of
miRNA-146a signaling and how it underlies common molecular-pathogenetic
mechanisms in each of these progressive, age-related neurological
disorders for which there are currently no effective treatment or cure.